This invention relates to novel heterocycle-substituted geminal diphosphonate compounds in which the diphosphonate moiety is attached to a carbon atom in a nitrogen-containing six membered ring heterocycle, preferably a piperidine ring. This invention further relates to pharmaceutical compositions containing these novel compounds. Finally, this invention relates to a method of treating or preventing diseases characterized by abnormal calcium and phosphate metabolism by utilizing a compound or pharmaceutical compositions of the present invention.
A number of pathological conditions which can afflict warm-blooded animals involves abnormal calcium and phosphate metabolism. Such conditions may be divided into two broad categories.
1. Conditions which are characterized by anomalous mobilization of calcium and phosphate leading to general or specific bone loss, or excessively high calcium and phosphate levels in the fluids of the body, such as osteoporosis and Paget's disease. Such conditions are sometimes referred to herein as pathological hard tissue demineralizations. PA1 2. Conditions which cause or result from deposition of calcium and phosphate anomalously in the body, such as arthritis. These conditions are sometimes referred to herein as pathological calcifications.
A variety of polyphosphonic acid derivatives have been proposed for use in the treatment and prophylaxis of diseases involving abnormal calcium and phosphate metabolism. For example, U.S. Pat. No. 3,683,080, issued Aug. 8, 1972 to Francis, discloses compositions containing polyphosphonates, in particular diphosphonates such as ethane-1-hydroxy-1,1-diphosphonic acid ("EHDP"), and their use in inhibiting anomalous deposition and mobilization of calcium and phosphate in animal tissue; U.S. Pat. No. 4,230,700, issued Oct. 28, 1980 to Francis, discloses compositions containing certain diphosphonates, including cycloalkyl-substituted hydroxy ethane diphosphonates, and vitamin D-like compounds for inhibiting mobilization of calcium phosphate in animal tissue; U.S. Pat. No. 4,267,108, issued May 12, 1981 to Blum et al, discloses 2'-pyrrolidine-1,1-hydroxymethane-1,1-diphosphonic acid said to be useful for treating diseases related to the abnormal deposition or dissolution of difficulty soluble calcium salts in the animal body; European Patent Application Publication No. 100,718, published Feb. 15, 1984 by Sanofi S. A., discloses pyridine-substituted thioalkane diphosphonates said to be useful for treating inflammatory diseases such as arthritis; European Patent Application Publication No. 170,228, published Feb. 5, 1986 by Boehringer Mannheim GmbH, discloses pyridine-substituted longer-chain alkane diphosphonates said to be useful for treating calcium metabolism disorders; and European Patent Application Publication No. 186,405, published Jul. 2, 1986 by Benedict and Perkins, discloses pyridine-substituted diphosphonates said to be useful for treating diseases characterized by abnormal calcium and phosphate metabolism. The disclosures of all these patents and applications are incorporated herein by reference in their entirety.
In addition, Unterspann, European Journal of Nuclear Medicine, 1 (3), pp 151-154 (1976), and Unterspann, Vortragssamml.-Nuklearmed. Syrup. 12th, Meeting Date 1975, pp 241-248 (1976; Klaus Schwartz, Editor) compare N-piperidinyl-methane-diphosphonic acid (a compound which is structurally similar to the compounds of the present invention) with other diphosphonate compounds, including EHDP, for Technetium-99m labelability and suitability for bone scintigraphy. The data obtained from these studies indicate that this compound has less skeleton activity than EHDP. Furthermore, Landeck and Binus, Stomatol. DDR, 30 (3), pp 169-175 (1980), apparently used the same compound to investigate the effect of parenteral administration of certain diphosphonates on the size and structure of hamsters' incisors. Little or no effect on the mineralization of the incisors was observed for hamsters treated with this compound.
It has been surprisingly discovered that the heterocycle-substituted diphosphonate compounds of the present invention, which have the diphosphonate moiety attached to a carbon atom in a nitrogen-containing six membered ring heterocycle (preferably a piperidine ring), have potent bone antiresorptive activity. This activity is significantly greater than EHDP. Thus, in spite of the above-noted and much other research into the use of diphosphonates to treat bone-metabolism diseases, there continues to be a need for potent new bone-active agents. It is therefore an object of the present invention to provide new bone-active diphosphonate compounds which are potent bone resorption inhibiting agents. It is a further object of the present invention to provide pharmaceutical compositions useful for the treatment and prophylaxis of abnormal calcium and phosphate metabolism. In addition, it is an object of the present invention to provide methods for treating or preventing diseases characterized by abnormal calcium and phosphate metabolism in humans or lower animals.
These and other objects of the present invention will become apparent from the detailed disclosure of the present invention provided hereinafter.